Methamphetamine (meth) addicts often exhibit enduring cognitive and neural deficits that likely contribute to persistent drug seeking and the high rates of relapse. These deficits may be related to changes in the prefrontal cortex (PFC) and its glutamatergic projections to the nucleus accumbens (NAc). Here, we performed in vivo microdialysis in the PFC and NAc in rats following either meth self-administration or yoked-saline control histories to assess baseline glutamate (GLU) levels, or reinstatement-evoked GLU and dopamine (DA) efflux in both regions simultaneously under cue-induced, meth-primed, or combined cues þ meth reinstatement conditions. Our results show that meth self-administration (1) reduced basal GLU levels in both the dmPFC and NAc, (2) concurrently increased dmPFC and NAc GLU efflux during reinstatement, and (3) increased DA efflux in the dmPFC, but not in the NAc, under all reinstatement conditions when compared with yoked-saline controls. These data demonstrate for the first time that a history of psychostimulant self-administration alters GLU homeostasis not only in the NAc, but also in the dmPFC, its primary GLU projection source. Furthermore, combined cues þ meth-primed reinstatement conditions produced the most pronounced increases in mPFC and NAc extracellular GLU, suggesting that the cue and meth prime conditions are additive in promoting reinstatement. Finally, increased efflux of DA in the dmPFC, but not in the NAc, across reinstatement conditions suggests that DA release in the dmPFC may be an important mediator of drug seeking initiated by multiple relapse triggers. Neuropsychopharmacology (2014) 39, 811-822; doi:10.1038/npp.2013; published online 9 October 2013 Keywords: dopamine; glutamate; methamphetamine self-administration; nucleus accumbens; prefrontal cortex; reinstatement
INTRODUCTIONThe development of drug addiction is believed to derive in large part from maladaptive neurobiological responses to drugs of abuse within the corticostriatal glutamate (GLU) and mesostriatal dopamine (DA) systems of the brain (Berridge and Robinson, 1998;Wise, 2004;Kalivas et al, 2005). Although these circuits normally optimize behavior in response to a changing environment and establish welllearned behaviors, their dysregulation due to repeated drug abuse likely underlies the switch to habitual drug-taking behaviors, which operate outside of normal cortical regulation (Goldstein et al, 2009;George and Koob, 2010).Methamphetamine (meth) addicts often exhibit pronounced deficits in cortical regulation of subcortical drive (Baicy and London, 2007;Salo et al, 2009). The impact of meth on this circuitry may be more profound than other addictive drugs, due in part to its long half-life, high-lipid solubility, fast uptake and accumulation, and distinctive pharmacological effects on both DA and GLU functions (Bowyer et al, 2008;Fowler et al, 2008;Stephans and Yamamoto, 1994). Thus, meth abuse may alter DA receptive pyramidal neurons in the PFC, in turn affecting downstream signaling in the nucleus accum...